A major goal of INIA-West is to identify novel therapeutics for excessive alcohol consumption and prior INIA-West efforts have identified and characterized rodent animal models of excessive intake, and candidate genes and associated targets that are altered in these models. The next iteration of INIA-West is directed at identifying which of these gene targets should be targeted for further analysis. Therefore, a simple yet functionally meaningful assay to test whether a target may exhibit efficacy for excessive ethanol intake would be extremely valuable. We and our co-investigators have developed substantial evidence that changes in glutamatergic synaptic plasticity in the nucleus accumbens constitute a critical neuroadaptive response to repeated exposure to positive and negative reinforcers. Furthermore, disruption of the processes underlying the changes in glutamate receptor location and function (GluR2 subunit internalization) modulates behavioral responses to such reinforcers. Therefore, we propose that accumbal plasticity constitutes exactly such a functionally meaningful assay. We propose two main hypotheses to investigate the utility of NAc plasticity as a functional screen for novel targets for ethanol dependence. In Specific Aim 1 we propose to identify how prolonged disruption of GluR2 subunit internalization in vivo modulates excessive ethanol intake using two models: CIE with two-bottle choice and operant ethanol self-administration. In Specific Aim 2 we propose to screen novel gene targets identified by INIA-West components for modulation of accumbal plasticity under baseline conditions and following CIE exposure. This aim will use the INIA-West RNA interference (RNAi) core and we will work in close coordination with our INIA-West colleagues who are focused upon detailed analyses of these individual INIA-West targets. Thus, in aim 2, we will determine whether interference with INIA-West target expression modulates NAc LTD. Finally, as we show in our preliminary data, NAc LTD is predominant in NAc MSNs ofthe direct pathway that express Dl-dopamine receptors, we will ensure that plasticity will be screened for all experiments in DI-NAc MSNs using mice derived from MIVIRRC GENSAT drdl-eGFP Swiss Webster mice back-crossed to the C57BI6/J background. PUBLIC HEALTH RELEVANCE: This project is designed to work within a larger research consortium to optimize the likelihood that novel therapeutics for the treatment of alcohol dependence are discovered. We propose to determine whether candidates alter brain functions implicated in the development of dependence to a variety of drugs of abuse.